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Safety & Efficacy of Daptomycin Versus Standard of Care (SOC) in 1 - 17 Year Olds With Staphylococcus Aureus Bacteremia (MK-3009-005)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Cubist Pharmaceuticals LLC
ClinicalTrials.gov Identifier:
NCT01728376
First received: November 5, 2012
Last updated: October 13, 2016
Last verified: October 2016
  Purpose
The intent of this study is to describe the safety and efficacy of daptomycin versus standard of care (SOC) in pediatric participants aged 1-17 years with bacteremia caused by Staphylococcus aureus (S. aureus).

Condition Intervention Phase
Bacteremia
Drug: Daptomycin
Drug: Comparator
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Comparative Evaluation of the Safety and Efficacy of Daptomycin Versus Standard of Care in Pediatric Subjects One - Seventeen Years of Age With Bacteremia Caused by Staphylococcus Aureus.

Resource links provided by NLM:


Further study details as provided by Cubist Pharmaceuticals LLC:

Primary Outcome Measures:
  • Number of Participants With One or More Adverse Events (AEs) [ Time Frame: Administration of first dose through the last follow-up visit (up to 77 days) ] [ Designated as safety issue: Yes ]
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.

  • Number of Participants With One or More Serious Adverse Events (SAEs) [ Time Frame: Administration of first dose through the last follow-up visit (up to 77 days) ] [ Designated as safety issue: Yes ]
    An SAE is any adverse experience occurring at any dose that results in any of the following outcomes: death, life threatening experience, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, or is considered to be an important medical event.

  • Percentage of Participants With Maximum Post-Baseline Creatine Phosphokinase (CPK) Elevations Above Upper Limit of Normal [ Time Frame: Baseline up to end of therapy visit (up to 49 days) ] [ Designated as safety issue: Yes ]
    Blood was drawn from baseline up to the end of therapy visit to determine the percentage of participants with maximum post-baseline CPK elevations above the upper limit of 500 Units Per Liter (U/L) .

  • Percentage of Participants With Sustained CPK Elevations [ Time Frame: Baseline up to end of therapy visit (up to 44 days) ] [ Designated as safety issue: Yes ]
    Blood was drawn from baseline up to the end of therapy visit to determine the percentage of participants with sustained CPK elevations, defined as two consecutive post-baseline values above the upper limit of normal (ULN)

  • Number of Participants With Abnormal Focused (Peripheral) Neurological Assessments at Test of Cure (TOC) [ Time Frame: TOC Safety Visit (up to 56 days) ] [ Designated as safety issue: Yes ]
    Focused neurological examinations were done at the TOC/Safety Visit. These examinations include assessments of sensation, pupillary reflex and tracking, peripheral reflexes (biceps, patellar tendon, ankle jerk and plantar response), muscle tone and strength (upper and lower limbs), coordination (finger to nose) and tremor of the hands/fingers.


Secondary Outcome Measures:
  • Percentage of Participants With Clinical Success at TOC/Safety Visit [ Time Frame: 7-14 days after the last dose of study medication (up to 56 days) ] [ Designated as safety issue: No ]
    Clinical success was determined by assessing resolution/improvement of signs and symptoms. An assessment of cure or improved is considered clinical success. Cure: resolution of clinically significant signs and symptoms associated with admission infection; no further antibiotic therapy is required for the primary infection under study. Improvement: partial resolution of clinical signs/symptoms of infection such that no further antibiotic therapy is required for the primary infection under study.

  • Percentage of Participants With Overall Success at TOC Visit [ Time Frame: 7-14 days after the last dose of study medication (up to 56 days) ] [ Designated as safety issue: No ]
    Overall success is based on microbiologic responses after initiating study drug and clinical response at TOC/Safety Visit. Overall outcome is a success if both clinical and microbiologic outcomes are successes. An assessment of cure or improved is considered clinical success. Microbiological Success: a participant for whom all baseline infecting pathogens were eradicated (presumed or documented) within 7 days from the start of study drug for uncomplicated bacteremia with no source of infection present, and 10 days for complicated bacteremia or when the source of infection has not been removed.

  • Trough Plasma Concentration of Daptomycin [ Time Frame: Days 3, 4, 5 or 6 of treatment at pre-dose ] [ Designated as safety issue: No ]
    Plasma concentrations of daptomycin were measured on Days 3 through 6 of IV dosing. Trough concentrations were collected 22 to 26 hours following the end of the previous day's end of infusion and before the next infusion. Concentrations below the limit of quantification were excluded.

  • Maximum Plasma Concentration (Cmax) of Daptomycin [ Time Frame: Days 3, 4, 5 or 6 of treatment at end of infusion ] [ Designated as safety issue: No ]
    Plasma concentrations of daptomycin were measured on Days 3 through 6 of IV dosing. Peak concentrations were collected up to 15 minutes following the end of infusion. Concentrations below the limit of quantification were excluded.


Enrollment: 82
Study Start Date: November 2012
Study Completion Date: January 2016
Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Daptomycin - 12 to 17 year olds
Participants ages 12-17 years old were administered daptomycin 7 mg/kg infused once daily, intravenously (IV), over 30 minutes; therapy duration (uncomplicated bacteremia) = 5-28 days, therapy duration (complicated bacteremia) = 7-42 days. After conclusion of IV therapy, can continue on oral therapy (not daptomycin, but at discretion of investigator).
Drug: Daptomycin
Intravenous daptomycin given at 7 mg/kg (ages 12-17 years); 9 mg/kg (ages 7-11 years); 12 mg/kg (ages 1-6 years) infused once daily, intravenously, over 30 or 60 minutes. Participants may be switched to oral therapy following completion of IV study drug administration provided they showed clear clinical improvement and the pathogen was susceptible to an oral agent.
Other Name: Cubicin
Active Comparator: Comparator - 12 to 17 year olds
Participants ages 12-17 years old received IV vancomycin or semi-synthetic penicillin or first-generation cephalosporins or clindamycin, given as per local guidelines or site-specific prescribing information; therapy duration (uncomplicated bacteremia) = 5-28 days, therapy duration (complicated bacteremia) = 7-42 days. IV comparator and subsequent oral therapy were at the discretion of the investigator.
Drug: Comparator
Vancomycin, Semi-synthetic penicillin, First-generation cephalosporins, Clindamycin: administered per standard of care. Participants may be switched to oral therapy following completion of IV study drug administration provided they showed clear clinical improvement and the pathogen was susceptible to an oral agent.
Experimental: Daptomycin - 7 to 11 year olds
Participants ages 7 to 11 years old were administered daptomycin 9 mg/kg, infused once daily, IV over 30 minutes; therapy duration (uncomplicated bacteremia) = 5-28 days, therapy duration (complicated bacteremia) = 7-28 days. After conclusion of IV therapy, can continue on oral therapy (not daptomycin, but at discretion of investigator).
Drug: Daptomycin
Intravenous daptomycin given at 7 mg/kg (ages 12-17 years); 9 mg/kg (ages 7-11 years); 12 mg/kg (ages 1-6 years) infused once daily, intravenously, over 30 or 60 minutes. Participants may be switched to oral therapy following completion of IV study drug administration provided they showed clear clinical improvement and the pathogen was susceptible to an oral agent.
Other Name: Cubicin
Experimental: Daptomycin - 1 to 6 year olds
Participants ages 1 to 6 years old were administered daptomycin 12 mg/kg, infused once daily, IV over 60 minutes; therapy duration (uncomplicated bacteremia) = 5-28 days, therapy duration (complicated bacteremia) = 7-28 days. After conclusion of IV therapy, can continue on oral therapy (not daptomycin, but at discretion of investigator).
Drug: Daptomycin
Intravenous daptomycin given at 7 mg/kg (ages 12-17 years); 9 mg/kg (ages 7-11 years); 12 mg/kg (ages 1-6 years) infused once daily, intravenously, over 30 or 60 minutes. Participants may be switched to oral therapy following completion of IV study drug administration provided they showed clear clinical improvement and the pathogen was susceptible to an oral agent.
Other Name: Cubicin
Active Comparator: Comparator - 7 to 11 year olds
Participants ages 7-11 years old received IV vancomycin, or semi-synthetic penicillin, or first-generation cephalosporins, clindamycin; given as per local guidelines or site-specific prescribing information; therapy duration (uncomplicated bacteremia) = 5-28 days, therapy duration (complicated bacteremia) = 7-28 days. IV comparator and subsequent oral therapy were at the discretion of the investigator.
Drug: Comparator
Vancomycin, Semi-synthetic penicillin, First-generation cephalosporins, Clindamycin: administered per standard of care. Participants may be switched to oral therapy following completion of IV study drug administration provided they showed clear clinical improvement and the pathogen was susceptible to an oral agent.
Active Comparator: Comparator - 1 to 6 year olds
Participants ages 1-6 years old received IV vancomycin, or semi-synthetic penicillin, or first-generation cephalosporins, clindamycin; given as per local guidelines or site-specific prescribing information; therapy duration (uncomplicated bacteremia) = 5-28 days, therapy duration (complicated bacteremia) = 7-28 days. IV comparator and subsequent oral therapy were at the discretion of the investigator.
Drug: Comparator
Vancomycin, Semi-synthetic penicillin, First-generation cephalosporins, Clindamycin: administered per standard of care. Participants may be switched to oral therapy following completion of IV study drug administration provided they showed clear clinical improvement and the pathogen was susceptible to an oral agent.

Detailed Description:

S. aureus causes a series of invasive diseases in adults and children, including bacteremia. Infections due to S. aureus in children, particularly those due to methicillin resistant S. aureus (MRSA), are a growing world-wide public health concern.

Daptomycin, a cyclic lipopeptide antibacterial agent, shows rapid in vitro bactericidal activity with concentration-dependent killing for Gram-positive organisms, including S. aureus. Surveillance studies have demonstrated a daptomycin MIC90 of 0.5µg/ml for both methicillin-susceptible S. aureus (MSSA) and MRSA with >99% of MRSA isolates being categorized as susceptible by the Food and Drug Administration (FDA), European Committee of antimicrobial susceptibility testing (EUCAST) and Clinical and Laboratory Standards Institute (CLSI) breakpoints (5). Clinical trials in adults demonstrated that daptomycin was safe and efficacious in complicated skin and skin structure infections (cSSSI) and bloodstream infections caused by S. aureus, including right-sided infective endocarditis (RIE). However, information on the safety and efficacy of daptomycin for use in children is lacking.

The intent of this study in children is to confirm the safety of daptomycin at mean steady state systemic exposures (AUC) similar to those reported for adults treated at 6 mg/kg for bacteremia.

  Eligibility

Ages Eligible for Study:   1 Year to 17 Years   (Child)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

To be included in this study, participants must:

  • Sign a parental consent form; if appropriate, sign an assent form
  • Be between 1 and 17 years of age
  • Have proven or probable bacteremia caused by S. aureus based on the traditional culture result, rapid diagnostic test or Gram stain
  • If female of childbearing potential, must not be pregnant or nursing and take appropriate measures to not get pregnant during the study
  • If male, must take appropriate measures to not get partner pregnant
  • Able to comply with the protocol requirements

Exclusion Criteria:

Participants will not be allowed into the study if they:

  • Have received a certain amount of antibacterial therapy specific for current bacteremia unless it is demonstrated that the organism is resistant to the given antibacterial;
  • Anticipate to require other antibiotics that may be potentially effective against S. aureus;
  • Have shock or hypotension unresponsive to standard therapy;
  • Have received an investigational product or have participated in an experimental procedure within 30 days;
  • Have an intolerance or hypersensitivity to daptomycin;
  • Have renal insufficiency;
  • Have prior history or current evidence of muscle damage (rhabdomyolysis; significant CPK elevation);
  • Have history of clinically significant muscular disease, nervous system or seizure disorder, including unexplained muscular weakness, history of peripheral neuropathy, Guillain-Barré or spinal cord injury;
  • Have S. aureus pneumonia, empyema, meningitis, or endocarditis
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01728376

Sponsors and Collaborators
Cubist Pharmaceuticals LLC
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.
  More Information

Responsible Party: Cubist Pharmaceuticals LLC
ClinicalTrials.gov Identifier: NCT01728376     History of Changes
Other Study ID Numbers: 3009-005  DAP-PEDBAC-11-02 
Study First Received: November 5, 2012
Results First Received: October 13, 2016
Last Updated: October 13, 2016
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Bacteremia
Bacterial Infections
Sepsis
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Daptomycin
Penicillins
Vancomycin
Cephalosporins
Clindamycin
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on December 09, 2016